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Alcohol Withdrawal Syndrome

Alcohol Alert From NIAAA

The alcohol withdrawal syndrome is a cluster of symptoms observed in persons who stop drinking alcohol following continuous and heavy consumption. Milder forms of the syndrome include tremulousness, seizures, and hallucinations, typically occurring within 6-48 hours after the last drink.

A more serious syndrome, delirium tremens (DTs), involves profound confusion, hallucinations, and severe autonomic nervous system overactivity, typically beginning between 48 and 96 hours after the last drink (Victor 1983). Estimates vary on the incidence of serious consequences of alcohol withdrawal. Regardless of actual incidence, recent evidence suggests that it may be important to treat everyone who is suffering from alcohol withdrawal.

In a classic study that has shaped our understanding of alcohol withdrawal for many years, Isbell et al. (1955) found that alcohol-related seizures occur only after stopping heavy drinking. In a recent study that looked primarily at seizures, Ng et al. (1988) challenged Isbell's concept and reported that the risk of first seizure is related to current alcohol use rather than to withdrawal.

They concluded, based on self-reports given retrospectively by seizure patients, that the relationship of alcohol use to seizures is causal and dose-dependent. However, emerging neurophysiological findings lend support to Isbell's interpretation of withdrawal.

When Alcohol is Withdrawn

In the central nervous system, ethanol (in concentrations high enough to intoxicate humans) interferes with the processes that tell certain nerve cells to activate or become excited (Hoffman et al. 1989; Lovinger et al. 1989). It also enhances those processes that tell certain nerve cells to be restrained (Suzdak et al. 1986). Thus, ethanol acts as a nonspecific biochemical inhibitor of activity in the central nervous system. During withdrawal, a person's central nervous system experiences a reversal of this effect: Excitatory processes are enhanced while inhibitory processes are reduced (Morrow et al. 1988). Such changes can result in overactivation of the central nervous system when alcohol is withdrawn.

Clinical researchers have measured this overactivation in patients (Linnoila et al. 1987). Even patients with moderately severe alcohol withdrawal can experience sympathetic nervous system overactivity and increased production of the adrenal hormones cortisol and norepinephrine. Both of these hormones can be toxic to nerve cells. Moreover, cortisol can specifically damage neurons in the hippocampus (Sapolsky et al. 1986)--a part of the brain that is thought to be particularly important for memory and control of affective states. Thus, repeated untreated alcohol withdrawals may lead to direct damage to the hippocampus.

Ballenger and Post (1978) did a retrospective chart review that led them to postulate that repeated inadequately treated withdrawals could produce future withdrawals of increased severity. These authors suggested that this phenomenon may be analogous to kindling as described in the animal literature.

Cumulative Effect of Withdrawals

In kindling, repeated, weak (subthreshold), electrical or pharmacological stimulation of certain parts of the central nervous system leads to increased sensitivity; an animal eventually exhibits behavioral changes (including seizures) that are more severe on each occasion. The implication is that repeated untreated withdrawals from alcohol have a cumulative effect and create more serious future withdrawals. Only a minority of chronic alcoholics develop a seizure disorder, so an inherited vulnerability may be involved.

Many investigators (e.g., Linnoila et al. 1987) now believe that chronic alcoholics who cannot maintain abstinence should receive pharmacotherapy to control withdrawal symptoms, thereby reducing the potential for further seizures and brain damage.

In a recent review of pharmacological treatments for alcohol intoxication, withdrawal, and dependence, Liskow and Goodwin (1987) concluded that the drugs of choice for treating withdrawal are the benzodiazepines--e.g., the longer-acting benzodiazepines chlordiazepoxide (Librium) and diazepam (Valium) or the shorter-acting benzodiazepines oxazepam (Serax) and lorazepam (Ativan).

Physicians traditionally have used benzodiazepines by administering decreasing doses over the period of alcohol withdrawal. Rosenbloom (1988) recommends this approach, suggesting the use of intermediate half-life benzodiazepines (such as lorazepam), or even shorter half-life drugs (such as midazolam), because these drugs do not linger in the system and allow for doses to be easily titrated to the parent's response.

Medications Prevent Seizures

However, Sellers et al. (1983) introduced a different approach. At the start of treatment, doses of diazepam are given every 1 to 2 hours until withdrawal symptoms abate. Because diazepam has a long half-life and produces a psychoactive metabolite (desmethyldiazepam) with an even longer half-life, there is usually no need for further medication.

This strategy, called "loading dose," simplifies treatment, protects against seizures, and eliminates possible reinforcement of drug-seeking behavior in parents who otherwise might receive additional medication for relief of symptoms.

Other agents, such as the beta-blocker propranolol (Sellers et al. 1977), the beta-blocker atenolol in combination with oxazepam (Kraus et al. 1985), and the alpha-2-adrenoreceptor agonist clonidine (Manhem et al. 1985; Robinson et al. 1989), have been tested and shown to alleviate some symptoms of the withdrawal syndrome, but there is no clear evidence of their efficacy in preventing seizures (Liskow and Goodwin 1987).

Potential drugs for future use are calcium channel blockers (Koppi et al. 1987) and carbamazepine, which are now in the early stages of evaluation (Butler & Messiha 1986).

Most clinicians use medications to diminish the symptoms of alcohol withdrawal. However, Whitfield et al. (1978) reported success with nondrug detoxification of a group of ambulatory patients with uncomplicated alcoholism. The treatment consisted of screening and providing extensive social support during withdrawal.

Treatment Programs

The authors concluded that nondrug detoxification offers a reduced need for medical staff, a shortened detoxification period, and no sedative interference with a patient's alertness for participating in an alcohol treatment program.

Several researchers have developed scales for assessing the severity of the alcohol withdrawal syndrome: the Total Severity Assessment and Selected Severity Assessment (Gross et al. 1973), the Abstinence Symptom Evaluation Scale (Knott et al. 1981), and the Clinical Institute Withdrawal Assessment Scale [CIWA] (Shaw et al. 1981) Originally developed as research tools for studying treatment efficacy, such scales are now finding clinical use.

Foy et al. (1988) demonstrated that a modified version of the CIWA can assist in guiding treatment and predicting patients at risk for severe alcohol withdrawal. Such scales also may be helpful when monitoring the adequacy of a loading dose of medication. However, rating procedures are not infallible, and an occasional patient will have a more severe reaction than the scale predicts. Rating procedures cannot replace the clinical judgment of medical staff.

Inpatient Detox More Effective

One final point deserves mention. A recent study by Hayashida et al. (1989) compared outpatient with inpatient detoxification. The research concluded that outpatient medical detoxification is "an effective, safe, and low-cost treatment for patients with mild-to-moderate symptoms of alcohol withdrawal."

However, the data from this study indicate that inpatient detoxification was more effective than outpatient detoxification: At the 6-month followup those treated as inpatients reported significantly greater improvement in their drinking behavior, despite having been measured as more impaired than the outpatient group at the time of admission. This point is not emphasized in the report.

Whereas outpatient detoxification may be cheaper for some alcoholics, it is not clear to what extent serious comorbidities, which may be undetected outside a hospital setting, may lead to more severe and expensive problems later.


Alcohol Withdrawal Syndrome-- A Commentary by
NIAAA Director Enoch Gordis, M.D.

A variety of techniques exist for managing alcohol withdrawal, some that involve pharmacotherapy with sedatives and some that do not. Based on current literature, it appears that it is probably safe to treat mild withdrawal without drugs. However, research on treating alcohol withdrawal is just beginning to accumulate. Recent research findings show a potential for central nervous system damage to patients who experience repeated withdrawals and suggest that all patients exhibiting alcohol withdrawal symptoms receive pharmacotherapy. As evidence increases, it may well be that pharmacotherapy becomes the recommended choice in all withdrawal cases. Therefore, it is vital that clinicians keep abreast of the literature to ensure that their patients receive the most up-to-date care.

When using sedatives to treat alcohol withdrawal, understanding the relative advantages and disadvantages of different drug administration techniques is important. Administering an initial dose of a long-acting benzodiazepine, like diazepam, with repeated doses every 2 hours until symptoms subside, then stopping the drug, simplifies treatment and frees patients and staff to focus on the recovery process, not drug dosage schedules.

However, this method could cause problems if sedation is found to complicate an existing medical condition, such as chronic obstructive pulmonary disease, because the drugs, or their metabolites, remain in the body for several days. On the other hand, by giving repeated doses of a short-acting benzodiazepine (e.g., oxazepam), probably for several days, if complications to medical conditions are found, the drugs can be easily stopped due to their rapid elimination by the body. But this regimen is less easily managed because medication must be given around the clock, and it could result in the patient and staff attending to the drug-taking regimen rather than to recovery.

In deciding which drug administration technique to use for individual patients, there is no substitute for a thorough medical evaluation. There is a welcome trend toward using the CIWA and other clinical scales for measuring withdrawal syndrome severity and for guiding drug treatment decisions; their use should be encouraged. However, no scaling instrument is infallible. Withdrawal severity scales should be used to complement, not replace, a thorough clinical evaluation of the patient's medical status.


References

BALLENGER, J.C. & Post, R.M. Kindling as a model for alcohol withdrawal syndromes. British Journal of Psychiatry 133: 1-14, 1978. * BUTLER, D. and Messiha, F.S. Alcohol Withdrawal and carbamazepine. Alcohol: An International Biomedical Journal 3(2): 113-129, 1986. * FOY, A,; March, S.; and Drinkwater, V. Use of an objective clinical scale in the assessment and management of alcohol withdrawal in a large general hospital. Alcoholism: Clinical and Experimental Research 12(3):360-364, 1988. * GROSS, M.M.; Lewis, E.; and Nagarajan, M. An improved quantitative system for assessing the acute alcoholic psychoses and related states (TSA and SSA). In: Gross, M.M., ed. Alcohol Intoxication and Withdrawal. Vol. 35. New York: Plenum Press, 1973. pp. 365-376. * HAYASHIDA, M.; Alterman, A.I.; McLellan, T.; O'Brien, C.P.; Purtill, J.J.; Volpicelli, J.R.; Ra phaelson, A.H.; and Hall, C.P. Comparative effectiveness and costs of inpatient and outpatient detoxification of patients with mild-to-moderate alcohol withdrawal syndrome. The New England Journal of Medicine 320(6): 358-365, 1989. * HOFFMAN, P.L.; Rabe, C.S.; Moses, F.; Tabakoff, B. N-methyl-D-asparate receptors and ethanol: Inhibition of calcium flux and cyclic GMP production. Journal of Neurochemistry. 52: 1937-1940, 1989. * ISBELL, H.; Fraser, H.F., Wikler, A.; Belleville, R.E.; and Eisenman, A.J. An experimental study of the etiology of "rum fits" and delirium tremens. Quarterly Journal of Studies on Alcohol 16: 1-33, 1955. * KNOTT, D.H.; Lerner, W.D.; Davis-Knott, T.; and Fink, R. Decision for alcohol detoxification: A method to standardize patient evaluation. Postgraduate Medicine 69(5): 65-78, 1981. *KOPPI, S.; Eberhardt, G.; Haller, R.; and König, P. Calcium-channel-blocking agent in the treatment of acute alcohol withdrawal--caroverine plus meprobamate in a randomized double-blind study. Neuropsychobiology 17(1-2): 49-52, 1987. *KRAUS, M.L.; Gottlieb, L.D.; Horwitz, R.I., and Anscher, M. Randomized clinical trial of atenolol in patients with alcohol withdrawal. The New England Journal of Medicine 313(15): 905-909, 1985. *LINNOILA, M.; Mefford, I.; Nutt, D.; and Adinoff, B. NIH Conference. Alcohol withdrawal and noradrenergic function. Annals of Internal Medicine 107(6):875-889, 1987. * LISKOW, B.I. & Goodwin, D.W. Pharmacological treatment of alcohol intoxication, withdrawal and dependence: A critical review. Journal of Studies on Alcohol 48(4): 356-370, 1987. * LOVINGER, D.M.; White, G.; and Wright, F.F. Ethanol inhibits NMDA-activated ion current in hippocampal neurones. Science 243(4899): 1721-1724, 1989. * MANHEM, P.; Nilsson, L.H.; Moberg, A.; Wadstein, J.; and Hökfelt, B. Alcohol Withdrawal: Effects of clonidine treatment on sympathetic activity, the renin-aldosterone system, and clinical symptoms. Alcoholism: Clinical and Experimental Research 9(3): 238-243, 1985. MORROW, A.L.; Suzdak, P.D.; Karanian, J.W.; and Paul, S.M. Chronic ethanol administration alters gamma-aminobutyric acid, pentobarbitol and ethanol-induced 36CL-uptake in cerebral cortical synaptoneurosomes. Journal of Pharmacology and Experimental Therapeutics 246(1): 158-164, 1988. * NG, S.K.C.; Hauser, W.A.; Brust, J.C.M.; and Susser, M. Alcohol consumption and withdrawal i new-onset seizures. The New England Journal of Medicine 319(11): 666-673, 1988. * ROBINSON, B.J.; Robinson, G.M.; Mailing, T.J.; and Johnson, R.H. Is clonidine useful in the treatment of alcohol withdrawal? Alcoholism: Clinical and Experimental Research 13(1): 95-98, 1989. * ROSENBLOOM, A. Emerging treatment options in the alcohol withdrawal syndrome. Journal of Clinical Psychiatry 49(12, Suppl.), 28-31, 1988. * SAPOLSKY, R.M.; Krey, L.C.; and McEwen, B.S. The neuroendocrinology of stress and aging: The glucocorticoid cascade hypothesis. Endocrine Reviews 7(3): 284-301, 1986. * SELLERS, E.M.; Naranjo, C.A.; Harrison, M.; Devenyi, P.; Roach, C.; and Sykora, K. Diazepam loading: Simplified treatment of alcohol withdrawal. Clinical Pharmacology Therapeutics 34(6): 822-826, 1983. * SELLERS, E.M.; Zilm, D.H.; and Degani, N.C. Comparative efficacy of propranolol and chlordiazepoxide in alcohol withdrawal. Journal of Studies on Alcohol 38(11): 2096-2108, 1977. * SHAW, J.M.; Kolesar, G.; Sellers, E.M.; Kaplan, H.L.; and Sandor, P. Development of optimal treatment tactics for alcohol withdrawal. I. Assessment of effectiveness of supportive care. Journal of Clinical Psychopharmacology 1(16): 382-389, 1981. * SUZDAK, P.D.; Glowa, J.R.; Crawley, J.N.; Schwartz, R.D.; Skolnik, P.; and Paul, S.M. A selective imidazobenzodiazepine antagonist of ethanol in the rat. Science 234(4781): 12243-1247, 1986. * VICTOR , M. Diagnosis and treatment of alcohol withdrawal states. Practical Gastroenterology 7(5): 6-15, 1983. * WHITFIELD, C.L.; Thompson, G.; Lamb, A.; Spencer, V.; Pfeifer, M.; and Browning-Ferrando, M. Detoxification of 1,024 alcohol patients without psychoactive drugs. Journal of the American Medical Association 239(14): 1409-1410, 1978.


NOTE: The following ERRATA appeared in Alcohol Alert No. 8. It is shown here for clarity.

ERRATA: Dr. M. Hayashida has notified NIAAA that Alcohol Alert No. 5, entitled "Alcohol Withdrawal Syndrome," contained incorrect information about his study comparing the effectiveness and costs of inpatient and outpatient detoxification (Hayashida, M.; Alterman, A.; McLellan, A.; et al. Comparative effectiveness and costs of inpatient and outpatient detoxification of patients with mild-to-moderate alcohol withdrawal syndrome. New England Journal of Medicine 320(6): 358-365,1989). The last paragraph of the Alert erroneously reported that data from the study provide evidence that inpatient detoxification was more effective than outpatient detoxification. However, an accurate interpretation of the study would have suggested that some significant differences were noted between the two groups at a 1-month followup, favoring inpatient detoxification (a group that was more impaired by some drinking measures at admission), but that no differences were observed at a 6-month followup.


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